Feeding and Fasting Signals Converge on the LKB1-SIK3 Pathway to Regulate Lipid Metabolism in Drosophila

LKB1 plays important roles in governing energy homeostasis by regulating AMP-activated protein kinase (AMPK) and other AMPK-related kinases, including the salt-inducible kinases (SIKs). However, the roles and regulation of LKB1 in lipid metabolism are poorly understood. Here we show that Drosophila LKB1 mutants display decreased lipid storage and increased gene expression of brummer, the Drosophila homolog of adipose triglyceride lipase (ATGL). These phenotypes are consistent with those of SIK3 mutants and are rescued by expression of constitutively active SIK3 in the fat body, suggesting that SIK3 is a key downstream kinase of LKB1. Using genetic and biochemical analyses, we identify HDAC4, a class IIa histone deacetylase, as a lipolytic target of the LKB1-SIK3 pathway. Interestingly, we found that the LKB1-SIK3-HDAC4 signaling axis is modulated by dietary conditions. In short-term fasting, the adipokinetic hormone (AKH) pathway, related to the mammalian glucagon pathway, inhibits the kinase activity of LKB1 as shown by decreased SIK3 Thr196 phosphorylation, and consequently induces HDAC4 nuclear localization and brummer gene expression. However, under prolonged fasting conditions, AKH-independent signaling decreases the activity of the LKB1-SIK3 pathway to induce lipolytic responses. We also identify that the Drosophila insulin-like peptides (DILPs) pathway, related to mammalian insulin pathway, regulates SIK3 activity in feeding conditions independently of increasing LKB1 kinase activity. Overall, these data suggest that fasting stimuli specifically control the kinase activity of LKB1 and establish the LKB1-SIK3 pathway as a converging point between feeding and fasting signals to control lipid homeostasis in Drosophila.

LKB1通过调控腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）及其他AMPK相关激酶（包括盐诱导激酶（salt-inducible kinases, SIKs）），在能量稳态调控中发挥重要作用。然而，目前关于LKB1在脂质代谢中的功能与调控机制尚不清楚。本研究发现，果蝇LKB1突变体的脂质储存量显著降低，且脂肪甘油三酯脂肪酶（adipose triglyceride lipase, ATGL）的果蝇同源基因brummer的表达水平显著上调。该表型与SIK3突变体的表型一致，且在果蝇脂肪体中表达组成型激活的SIK3可逆转该表型，提示SIK3是LKB1的关键下游激酶。通过遗传与生化分析，我们鉴定出IIa类组蛋白去乙酰化酶HDAC4为LKB1-SIK3通路的脂解靶点。有趣的是，本研究发现LKB1-SIK3-HDAC4信号轴受饮食状态调控。在短期禁食条件下，与哺乳动物胰高血糖素通路同源的脂动激素（adipokinetic hormone, AKH）通路可通过降低SIK3 Thr196位点的磷酸化水平抑制LKB1的激酶活性，进而诱导HDAC4核定位与brummer基因的表达上调。但在长期禁食条件下，不依赖AKH的信号通路会降低LKB1-SIK3通路的活性以诱导脂解反应。我们还发现，与哺乳动物胰岛素通路同源的果蝇胰岛素样肽（Drosophila insulin-like peptides, DILPs）通路，可在进食状态下调控SIK3的活性，且该过程不依赖于LKB1激酶活性的提升。综上，本研究数据表明，禁食刺激可特异性调控LKB1的激酶活性，并确立LKB1-SIK3通路作为进食与禁食信号的汇聚节点，以调控果蝇体内的脂质稳态。